Digital Commons Network^™

Mature Microrna-Binding Protein Qki Suppresses Extracellular Microrna Let-7b Release, Kyung-Won Min, Kyoung-Min Choi, Hyejin Mun, Seungbeom Ko, Ji Won Lee, Cari A Sagum, Mark T Bedford, Young-Kook Kim, Joe R Delaney, Jung-Hyun Cho, Ted M Dawson, Valina L Dawson, Waleed Twal, Dong-Chan Kim, Clarisse H Panganiban, Hainan Lang, Xin Zhou, Seula Shin, Jian Hu, Tilman Heise, Sang-Ho Kwon, Dongsan Kim, Young Hwa Kim, Sung-Ung Kang, Kyungmin Kim, Sydney Lewis, Ahmet Eroglu, Seonghyun Ryu, Dongin Kim, Jeong Ho Chang, Junyang Jung, Je-Hyun Yoon

Faculty, Staff and Student Publications

Argonaute (AGO), a component of RNA-induced silencing complexes (RISCs), is a representative RNA-binding protein (RBP) known to bind with mature microRNAs (miRNAs) and is directly involved in post-transcriptional gene silencing. However, despite the biological significance of miRNAs, the roles of other miRNA-binding proteins (miRBPs) remain unclear in the regulation of miRNA loading, dissociation from RISCs and extracellular release. In this study, we performed protein arrays to profile miRBPs and identify 118 RBPs that directly bind to miRNAs. Among those proteins, the RBP quaking (QKI) inhibits extracellular release of the mature microRNA let-7b by controlling the loading of let-7b into extracellular …

Mechanisms Of Resistance To Oncogenic Kras Inhibition In Pancreatic Cancer, Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre

Faculty, Staff and Student Publications

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. …

Effects Of Tranexamic Acid On Human Osteoblasts As Proxy For Fracture Healing, Alexander Abraham, D Nicole Meyers, William D Rieger, Ryan Anthony, Humberto Aparicio, Adam Y Park, James F Kellam, Catherine G Ambrose

Faculty, Staff and Student Publications

Objectives: To investigate the effect of tranexamic acid (TXA) through in vitro culture of primary human osteoblasts (HOB) and in vivo using an operative rat femur fracture model. It was hypothesized that there would not be any effect on fracture healing in both studies.

Methods: Primary HOBs were exposed to varying concentrations of TXA over different time periods. Cells were assessed for viability, metabolism, and mineralization. For the in vivo model, fractures were created in the femora of adult rats, exposed to either TXA or saline, and then assessed for healing at different time points. A modified radiographic union score …

Exposure To Statin Therapy Decreases The Incidence Of Venous Thromboembolism After Trauma, Kelly E Sanders, Gabrielle E Hatton, Atharwa R Mankame, Addison C Allen, Sarah Cunningham, Jan Michael Van Gent, Erin E Fox, Xu Zhang, Charles E Wade, Bryan A Cotton, Jessica C Cardenas

Faculty, Staff and Student Publications

Introduction: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in trauma patients, despite chemoprophylaxis. Statins have been shown capable of acting upon the endothelium. We hypothesized that statin therapy in the pre- or in-hospital settings leads to a decreased incidence of VTE.

Methods: We conducted a retrospective cohort study of injured patients who received statin therapy pre- or in-hospital. Adult, highest-level trauma activation patients admitted from January 2018 to June 2022 were included. Patients on prehospital anticoagulants, had history of inherited bleeding disorder, and who died within the first 24 hours were excluded. Statin users were matched …

The Effect Of Smoking On Functional Outcomes And Implant Survival Of Anatomical Total Shoulder Arthroplasty, Isabella E Amador, Kevin A Hao, Timothy R Buchanan, Derek S Damrow, Keegan M Hones, Trevor Simcox, Bradley S Schoch, Kevin W Farmer, Thomas W Wright, Tyler J Lamonica, Joseph J King, Jonathan O Wright

Faculty, Staff and Student Publications

Aims: We sought to compare functional outcomes and survival between non-smokers, former smokers, and current smokers who underwent anatomical total shoulder arthroplasty (aTSA) in a large cohort of patients.

Methods: A retrospective review of a prospectively collected shoulder arthroplasty database was performed between August 1991 and September 2020 to identify patients who underwent primary aTSA. Patients were excluded for preoperative diagnoses of fracture, infection, or oncological disease. Three cohorts were created based on smoking status: non-smokers, former smokers, and current smokers. Outcome scores (American Shoulder and Elbow Surgeons (ASES), Constant-Murley score, Shoulder Pain and Disability Index (SPADI), Simple Shoulder Test …

Increased Gremlin1 Expression In Pancreatic Ductal Adenocarcinoma Promotes A Fibrogenic Stromal Microenvironment, Rachel R Tindall, Erika Y Faraoni, Jiajing Li, Yinjie Zhang, Shun-Ming Ting, Beanna Okeugo, Xiurong Zhao, Yuying Liu, Mamoun Younes, Qiang Shen, Jennifer M Bailey-Lundberg, Yanna Cao, Tien C Ko

Faculty, Staff and Student Publications

Objective: Pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not defined.

Materials and methods: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas RNA-sequencing data and characterized expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies.

Results: Grem1 expression is associated with an activated stroma and …

Increased White Blood Cell In Young Adults With Family Histories Of Alcohol And Other Substance Use Disorders, Mustafa N Mithaiwala, Nikki S Phillips, Dylan H Nguyen, Melanie S Beehler, Harrison S Ballard, Andrea S Vincent, William R Lovallo, Peter Kochunov, L Elliot Hong, Jason C O'Connor, Steve Cole, Ashley Acheson

Faculty, Staff and Student Publications

Individuals with a family history of alcohol or other substance use disorders (FH+) are at increased risk for developing alcohol and other substance use disorders (AUD/SUD) compared to individuals with no such family histories (FH-). FH+ young adults have blunted stress reactivity, lower cognitive performance and altered frontal white matter microstructure compared to FH- controls. We hypothesized that family history of AUD/SUD disrupts neuroendocrine regulation of the immune system in FH+ individuals, resulting in altered blood immune cell composition, inflammation and neurocognitive alterations that, ultimately, increases risk for AUD/SUD and associated psychopathology. We examined white blood cell (WBC) parameters derived …

Discovery, Characterization, And Structure Of A Cofactor-Independent Histidine Racemase From The Oral Pathogen Fusobacterium Nucleatum, Tess Lamer, Pu Chen, Marie J Venter, Marco J Van Belkum, Anjalee Wijewardane, Chenggang Wu, M Joanne Lemieux, John C Vederas

Faculty, Staff and Student Publications

Fusobacterium nucleatum is an oral commensal bacterium that can act as an opportunistic pathogen and is implicated in diseases such as periodontitis, adverse pregnancy outcomes, colorectal cancer, and Alzheimer's disease. F. nucleatum synthesizes lanthionine for its peptidoglycan, rather than meso-2,6-diaminopimelic acid (DAP) used by most Gram-negative bacteria. Despite lacking the biosynthetic pathway for DAP, the genome of F. nucleatum ATCC 25586 encodes a predicted DAP epimerase. A recent study hypothesized that this enzyme may act as a lanthionine epimerase, but the authors found a very low turnover rate, suggesting that this enzyme likely has another more favored substrate. Here, we …

Glymphatic Dysfunction In Multiple Sclerosis And Its Association With Disease Pathology And Disability, Ahmed Bayoumi, Khader M Hasan, Joseph A Thomas, Akram Yazdani, John A Lincoln

Faculty, Staff and Student Publications

Background: The role of the glymphatic system in multiple sclerosis (MS)-related disability remains underexplored. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) offers a non-invasive method to assess glymphatic function.

Objective: To evaluate glymphatic function in MS patients with lower and higher disability.

Methods: This study included 118 MS patients who underwent structural, diffusion-weighted imaging, and clinical assessment. The participants were divided into lower (MS-L, n = 57) and higher disability (MS-H, n = 61) subgroups. Brain parenchymal fraction (BPF), lesion load (LL), and DTI-ALPS index were measured. Subgroup differences and correlations between DTI-ALPS index and other measures were explored. …

A Novel Statistical Framework For Meta-Analysis Of Total Mediation Effect With High-Dimensional Omics Mediators In Large-Scale Genomic Consortia, Zhichao Xu, Peng Wei

Faculty, Staff and Student Publications

Meta-analysis is used to aggregate the effects of interest across multiple studies, while its methodology is largely underexplored in mediation analysis, particularly in estimating the total mediation effect of high-dimensional omics mediators. Large-scale genomic consortia, such as the Trans-Omics for Precision Medicine (TOPMed) program, comprise multiple cohorts with diverse technologies to elucidate the genetic architecture and biological mechanisms underlying complex human traits and diseases. Leveraging the recent established asymptotic standard error of the R-squared (R2)-based mediation effect estimation for high-dimensional omics mediators, we have developed a novel meta-analysis framework requiring only summary statistics and allowing inter-study heterogeneity. Whereas the proposed …

Fusobacterium Nucleatum Abundance Is Associated With Cachexia In Colorectal Cancer Patients: The Colocare Study, Mmadili N Ilozumba, Adetunji T Toriola, Et Al.

2020-Current year OA Pubs

BACKGROUND: Cachexia accounts for about 20% of all cancer-related deaths and indicates poor prognosis. The impact of Fusobacterium nucleatum (Fn), a microbial risk factor for colorectal cancer (CRC), on the development of cachexia in CRC has not been established.

METHODS: We evaluated the association between Fn abundance in pre-surgical stool samples and onset of cachexia at 6 months post-surgery in n = 87 patients with stages I-III CRC in the ColoCare Study.

RESULTS: High fecal Fn abundance compared to negative/low fecal Fn abundance was associated with 4-fold increased risk of cachexia onset at 6 months post-surgery (OR = 4.82, 95% …

Shear Stress Induces A Time-Dependent Inflammatory Response In Human Monocyte-Derived Macrophages, Elysa Jui, Griffin Kingsley, Hong Kim T Phan, Kavya L Singampalli, Ravi K Birla, Jennifer P Connell, Sundeep G Keswani, K Jane Grande-Allen

Faculty, Staff and Students Publications

Macrophages are innate immune cells that are known for their extreme plasticity, enabling diverse phenotypes that lie on a continuum. In a simplified model, they switch between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes depending on surrounding microenvironmental cues, which have been implicated in disease outcomes. Although considerable research has been focused on macrophage response to biochemical cues and mechanical signals, there is a scarcity of knowledge surrounding their behavior in response to shear stress. In this study, we applied varying magnitudes of shear stress on human monocyte-derived macrophages (MDMs) using a cone-and-plate viscometer and evaluated changes in morphology, gene expression, …

Metabolic Stress Induces A Double-Positive Feedback Loop Between Ampk And Sqstm1/P62 Conferring Dual Activation Of Ampk And Nfe2l2/Nrf2 To Synergize Antioxidant Defense, Eun-Ji Choi, Hyun-Taek Oh, Seon-Hyeong Lee, Chen-Song Zhang, Mengqi Li, Soo-Youl Kim, Sunghyouk Park, Tong-Shin Chang, Byung-Hoon Lee, Sheng-Cai Lin, Sang-Min Jeon

Staff and Researcher Publications

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, …

Suppression Of Matrigel-Induced Choroidal Neovascularization By Aav Delivery Of A Novel Anti-Scg3 Antibody, Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Efforts to develop gene therapy for long-term treatment of neovascular disease are hampered by ongoing concerns that biologics against vascular endothelial growth factor (VEGF) inhibit both physiological and pathological angiogenesis and are therefore at elevated risk of adverse side effects. A potential solution is to develop disease-targeted gene therapy. Secretogranin III (Scg3), a unique disease-restricted angiogenic factor described by our group, contributes significantly to ocular neovascular disease. We have shown that Scg3 blockade with a monoclonal antibody Fab fragment (Fab) stringently inhibits pathological angiogenesis without affecting healthy vessels. Here we tested the therapeutic efficacy of adeno-associated virus (AAV)-anti-Scg3Fab to block …

A Cross-Systems Primer For Synthetic Microbial Communities, Elijah C Mehlferber, Gontran Arnault, Bishnu Joshi, Laila P Partida-Martinez, Kathryn A Patras, Marie Simonin, Britt Koskella

Faculty, Staff and Students Publications

The design and use of synthetic communities, or SynComs, is one of the most promising strategies for disentangling the complex interactions within microbial communities, and between these communities and their hosts. Compared to natural communities, these simplified consortia provide the opportunity to study ecological interactions at tractable scales, as well as facilitating reproducibility and fostering interdisciplinary science. However, the effective implementation of the SynCom approach requires several important considerations regarding the development and application of these model systems. There are also emerging ethical considerations when both designing and deploying SynComs in clinical, agricultural or environmental settings. Here we outline current …

Bcl-Xl Is Translocated To The Nucleus Via Ctbp2 To Epigenetically Promote Metastasis, Tiantian Zhang, Sha Li, Yingcai Adrian Tan, Xiang Chen, Cheryl Zhang, Zhengming Chen, Bikash Mishra, Joseph Hyungjoon Na, Soyoung Choi, Sandra J Shin, Priyadarshan Damle, Kranthi Kumar Chougoni, Steven R Grossman, Dunrui Wang, Xuejun Jiang, Yi Li, Erika Hissong, Yao-Tseng Chen, Jenny Z Xiang, Yi-Chieh Nancy Du

Faculty, Staff and Students Publications

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and …

Genetic Risk Factors In Isolated Dystonia Escape Genome-Wide Association Studies, Björn-Hergen Laabs, Katja Lohmann, Eva-Juliane Vollstedt, Tobias Reinberger, Lisa-Marie Nuxoll, Gamze Kilic-Berkmen, Joel S Perlmutter, Sebastian Loens, Carlos Cruchaga, Andre Franke, Valerija Dobricic, Frauke Hinrichs, Anne Grözinger, Eckart Altenmüller, Steven Bellows, Sylvia Boesch, Susan B Bressman, Kevin R Duque, Alberto J Espay, Andreas Ferbert, Jeanne S Feuerstein, Samuel Frank, Thomas Gasser, Bernhard Haslinger, Robert Jech, Frank Kaiser, Christoph Kamm, Katja Kollewe, Andrea A Kühn, Mark S Ledoux, Ebba Lohmann, Abhimanyu Mahajan, Alexander Münchau, Trisha Multhaupt-Buell, Alexander Pantelyat, Sarah E Pirio Richardson, Deborah Raymond, Stephen G Reich, Rachel Saunders Pullman, Barbara Schormair, Nutan Sharma, Azadeh Hamzehei Sichani, Kristina Simonyan, Jens Volkmann, Aparna Wagle Shukla, Juliane Winkelmann, Laura J Wright, Michael Zech, Kirsten E Zeuner, Simone Zittel, Meike Kasten, Yan V Sun, Tobias Bäumer, Norbert Brüggemann, Laurie J Ozelius, Hyder A Jinnah, Christine Klein, Inke R König

Faculty, Staff and Students Publications

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia.

Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia.

Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation.

Results: This GWAS identified no common genome-wide significant …

Assessing The Relative Efficacy Of Components Of Opioid-Free Anaesthesia In Adult Surgical Patients: Protocol For A Systematic Review And Component Network Meta-Analysis, Amparo Belltall, Guido Mazzinari, Aisling Ní Eochagáin, Tom Wall, Ary Serpa Neto, Oscar Diaz-Cambronero, Daniel Sessler, Donal J Buggy, Juan Cata, Markus W Hollmann

Faculty, Staff and Student Publications

Introduction: The rise of opioid-free anaesthesia (OFA) aims to reduce postoperative pain while reducing opioid-related side effects during surgery. However, the various adjuvant agents used in OFA complicate the evaluation of their effectiveness and risks. Recent reviews question the clinical benefits of OFA, highlighting the need for thorough evaluation. This protocol describes a network meta-analysis to compare the effectiveness of OFA with opioid-based anaesthesia and will identify key components for optimal postoperative outcomes.

Methods and analysis: We will perform a systematic search of literature published in English without time restriction in Embase, The Cochrane Library, MEDLINE (via PubMed) and CINAHL, …

Short-Term Outcomes Of A Healthy Relationship Intervention For The Prevention Of Sexual Harassment And Sexual Assault In The Us Military: Pilot Pretest-Postest Study, Belinda Hernandez, Ross Shegog, Christine Markham, Susan Emery, Elizabeth Baumler, Laura Thormaehlen, Rejane Andina Teixeira, Yanneth Rivera, Olive Pertuit, Chelsey Kanipe, Iraina Witherspoon, Janis Doss, Victor Jones, Melissa Peskin

Faculty, Staff and Student Publications

BACKGROUND: Sexual harassment (SH) and sexual assault (SA) are serious public health problems among US service members. Few SH and SA prevention interventions have been developed exclusively for the military. Code of Respect (X-CoRe) is an innovative web-based, multilevel, SA and SH intervention designed exclusively for the active-duty Air Force. The program's goal is to increase Airmen's knowledge and skills to build and maintain respectful relationships, ultimately reducing SH and SA and enhancing Airmen's overall well-being and mission readiness.

OBJECTIVE: This pilot study aimed to assess the short-term psychosocial impact (eg, knowledge, attitudes, and self-efficacy) of the web-based component of …

Mutational Scanning Of Crx Classifies Clinical Variants And Reveals Biochemical Properties Of The Transcriptional Effector Domain, James L Shepherdson, David M Granas, Jie Li, Zara Shariff, Stephen P Plassmeyer, Alex S Holehouse, Michael A White, Barak A Cohen

2020-Current year OA Pubs

The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human

Specialized Contact Sites Regulate The Fusion Of Chlamydial Inclusion Membranes, Christine Linton, Jordan Wesolowski, Anna Lobley, Toshiyuki Yamaji, Kentaro Hanada, Fabienne Paumet

Department of Microbiology and Immunology Faculty Papers

The intracellular bacterial pathogen Chlamydia trachomatis replicates within a membrane-bound compartment called the inclusion. Upon infection with several chlamydiae, each bacterium creates its own inclusion, resulting in multiple inclusions within each host cell. Ultimately, these inclusions fuse together in a process that requires the chlamydial protein IncA. Here, we show that inclusions form unique contact sites (inclusion contact sites, ICSs) prior to fusion, that serve as fusogenic platforms in which specific lipids and chlamydial proteins concentrate. Fusion depends on IncA clustering within ICSs and is regulated by PI(3,4)P₂ and sphingolipids. As IncA concentrates within ICSs, its C-terminus likely interacts …

Ten Challenges And Opportunities In Computational Immuno-Oncology, Riyue Bao, Alan Hutson, Anant Madabhushi, Vanessa D Jonsson, Spencer R Rosario, Jill S Barnholtz-Sloan, Elana J Fertig, Himangi Marathe, Lyndsay Harris, Jennifer Altreuter, Qingrong Chen, James Dignam, Andrew J Gentles, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Erika Kim, Mark Long, Martin Morgan, Eytan Ruppin, David Van Valen, Hong Zhang, Natalie Vokes, Daoud Meerzaman, Song Liu, Eliezer M Van Allen, Yi Xing

Faculty, Staff and Student Publications

Immuno-oncology has transformed the treatment of cancer, with several immunotherapies becoming the standard treatment across histologies. Despite these advancements, the majority of patients do not experience durable clinical benefits, highlighting the imperative for ongoing advancement in immuno-oncology. Computational immuno-oncology emerges as a forefront discipline that draws on biomedical data science and intersects with oncology, immunology, and clinical research, with the overarching goal to accelerate the development of effective and safe immuno-oncology treatments from the laboratory to the clinic. In this review, we outline 10 critical challenges and opportunities in computational immuno-oncology, emphasizing the importance of robust computational strategies and interdisciplinary …

An Autonomous Implantable Device For The Prevention Of Death From Opioid Overdose, Joanna L Ciatti, Victoria E Brings, Brian Ruyle, Michael R Talcott, Prashant Gupta, Richard A Slivicki, Nicolas Massaly, Michael C Montana, Mitchell Pet, Jose A Morón, Robert W Gereau, Et Al.

2020-Current year OA Pubs

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, now a leading cause of mortality among young people aged 18 to 45 years. At overdose levels, opioid-induced respiratory depression becomes fatal without the administration of naloxone within minutes. Currently, overdose survival relies on bystander intervention, requiring a nearby person to find the overdosed individual and have immediate access to naloxone to administer. To circumvent the bystander requirement, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose while simultaneously contacting first responders. We present three Naloximeter platforms, for fundamental research …

Pclaf-Dream Drives Alveolar Cell Plasticity For Lung Regeneration, Bongjun Kim, Yuanjian Huang, Kyung-Pil Ko, Shengzhe Zhang, Gengyi Zou, Jie Zhang, Moon Jong Kim, Danielle Little, Lisandra Vila Ellis, Margherita Paschini, Sohee Jun, Kwon-Sik Park, Jichao Chen, Carla Kim, Jae-Il Park

Faculty, Staff and Student Publications

Cell plasticity, changes in cell fate, is crucial for tissue regeneration. In the lung, failure of regeneration leads to diseases, including fibrosis. However, the mechanisms governing alveolar cell plasticity during lung repair remain elusive. We previously showed that PCLAF remodels the DREAM complex, shifting the balance from cell quiescence towards cell proliferation. Here, we find that PCLAF expression is specific to proliferating lung progenitor cells, along with the DREAM target genes transactivated by lung injury. Genetic ablation of Pclaf impairs AT1 cell repopulation from AT2 cells, leading to lung fibrosis. Mechanistically, the PCLAF-DREAM complex transactivates CLIC4, triggering TGF-β signaling activation, …

Professional Development: A Mixed Methods Study Of Masters Of Public Health Alumni, Orna Baron-Epel, Yana Douvdevany, Dana Ivancovsky-Wajcman, Paul Barach, Osnat Bashkin, Katarzyna Czabanowska, Keren Dopelt, Nadav Davidovitch, Szczepan Jakubowski, Fiona Macleod, Maureen Malowany, Leah Okenwa-Emegwa, Maya Peled-Raz, Shira Zelber-Sagi

College of Population Health Faculty Papers

INTRODUCTION: We examined the perceptions of the Master of Public Health (MPH) degree graduates regarding their personal competencies, job performance and professional development using a mixed method, explanatory sequential design.

METHODS: A cross-sectional, self-administered questionnaire of the Haifa School of Public Health alumni who graduated between 2005 and 2022 was disseminated to 849 graduates between March and June 2022, from which 127 responded (response rate: 14.90%). This was followed by 24 in-depth interviews with alumni from the same sample (conducted between November 2022 and March 2023).

RESULTS: The sample included 74.8% of females with a mean age of 40.7 years, …

Recovery After Human Bone Marrow Mesenchymal Stem Cells (Hbm-Mcs)-Derived Extracellular Vesicles (Evs) Treatment In Post-Mcao Rats Requires Repeated Handling, Yolanda Gomez-Galvez, Malvika Gupta, Mandeep Kaur, Salvatore Fusco, Maria Vittoria Podda, Claudio Grassi, Amit K. Srivastava, Lorraine Iacovitti, Elena Blanco-Suarez

Farber Institute for Neuroscience Faculty Papers

Rehabilitation is the only current intervention that improves sensorimotor function in ischemic stroke patients, similar to task-specific intensive training in animal models of stroke. Bone marrow mesenchymal stem cells (BM-MSCs)-derived extracellular vesicles (EVs) are promising in restoring brain damage and function in stroke models. Additionally, the non-invasive intranasal route allows EVs to reach the brain and target specific ischemic regions. Yet unclear is how handling might enhance recovery or influence other therapies such as EVs after stroke. We used the transient middle cerebral artery occlusion (MCAO) model of stroke in rats to assess how intensive handling alone, in the form …

Α4 Nicotinic Acetylcholine Receptors In Lipopolysaccharide-Related Lung Inflammation, J. Ritzenthaler, Walter H. Watson, Jesse Roman

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

Sepsis remains an important healthcare challenge. The lungs are often affected in sepsis, resulting in acute lung injury characterized by inflammation. Mechanisms involving lipopolysaccharide (LPS) stimulation of toll-like receptor (TLR) signaling with induction of proinflammatory pathways have been implicated in this process. To date, however, studies targeting these pathways have failed to improve outcomes. We have found that LPS may also promote lung injury through the activation of α4 nicotinic acetylcholine receptors (α4 nAChRs) in immune cells. We observed increased expression of α4 nAChRs in human THP-1 monocytic cells exposed to LPS (100 ng/mL, 24 h). We also observed that …

Policy-Relevant Differences Between Secondhand And Thirdhand Smoke: Strengthening Protections From Involuntary Exposure To Tobacco Smoke Pollutants, Georg E Matt, Lydia Greiner, Rachael A Record, Heather Wipfli, Jamie Long, Nathan G Dodder, Eunha Hoh, Nicolas Lopez Galvez, Thomas E Novotny, Penelope J E Quintana, Hugo Destaillats, Xiaochen Tang, Antoine M Snijders, Jian-Hua Mao, Bo Hang, Suzaynn Schick, Peyton Jacob, Prue Talbot, E Melinda Mahabee-Gittens, Ashley L Merianos, Thomas F Northrup, Lara Gundel, Neal L Benowitz

Faculty, Staff and Student Publications

Starting in the 1970s, individuals, businesses and the public have increasingly benefited from policies prohibiting smoking indoors, saving thousands of lives and billions of dollars in healthcare expenditures. Smokefree policies to protect against secondhand smoke exposure, however, do not fully protect the public from the persistent and toxic chemical residues from tobacco smoke (also known as thirdhand smoke) that linger in indoor environments for years after smoking stops. Nor do these policies address the economic costs that individuals, businesses and the public bear in their attempts to remediate this toxic residue. We discuss policy-relevant differences between secondhand smoke and thirdhand …

Health Risks Associated With Adopting New-Generation Disposable Products Among Young Adults Who Use E-Cigarettes, Shuyao Ran, James J Yang, Megan E Piper, Hsien-Chang Lin, Anne Buu

Faculty, Staff and Student Publications

New-generation disposable e-cigarettes have become increasingly popular among young adults in the USA since the FDA's partial flavor ban. This study aims to examine longitudinal changes in health risks among young adults who adopted these novel products, as well as the health effects of device types beyond the effects of other important e-cigarette characteristics. This study recruited e-cigarette users via voluntary response sampling from three college campuses in the USA to respond to four-wave online surveys conducted in four consecutive semesters. Among the participants who adopted disposables during the study, their health risks (dependence symptoms, respiratory symptoms, combustible tobacco use) …

Developing The ‘Life Threads’ Approach To Support Families After Traumatic Brain Injury In Uk Community Settings: Protocol For A Qualitative Pre-Feasibility Study., Charlotte Whiffin, Caroline Ellis-Hill, Alyson Norman, Morag Lee, Pam Singh, Jo Clark-Wilson, Audrey Daisley, Natasha Yasmin, Mark Holloway, Sara Rose, Fergus Gracey

School of Psychology

INTRODUCTION: Traumatic brain injury (TBI) brings about inevitable and significant changes for family members. Mental health effects for family members are well documented but there are significant gaps in support options across services. Here, we describe our protocol for a study that seeks to investigate the potential for a narrative, creative approach, the 'Life Threads' approach, as a low intensity, accessible means of support that can be applied across service contexts.

METHODS: We will recruit 20 family members of someone who sustained a TBI from services in an area of the UK with a diverse demographic. Family members will be …